16-7595618-G-C

Variant names:

• chr16-7595618-G-C
• NM_018723.4:c.538G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018723.4(RBFOX1):​c.538G>C​(p.Val180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

Genes affected

RBFOX1 (HGNC:18222): (RNA binding fox-1 homolog 1) The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24421775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.538G>C	p.Val180Leu	missense_variant	Exon 8 of 16	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.598G>C	p.Val200Leu	missense_variant	Exon 5 of 14	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.538G>C	p.Val180Leu	missense_variant	Exon 8 of 16	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.598G>C	p.Val200Leu	missense_variant	Exon 5 of 14	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428424 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 709656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.14e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	.;.;.;T;.;T;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.036
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.86	.;.;L;L;.;.;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	.;N;N;N;N;N;N;N;N;N;N;N;N;.;.
REVEL	Benign	0.10
Sift	Benign	0.11	.;T;T;T;D;T;D;T;T;T;T;T;T;.;.
Sift4G	Benign	0.13	.;T;T;T;D;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.023, 0.24, 0.062, 0.026, 0.93, 0.98	.;.;B;B;B;B;.;.;B;B;P;D;.;.;.
Vest4		0.20, 0.18, 0.20, 0.19, 0.22, 0.21, 0.20, 0.19, 0.21
MutPred		0.40		.;.;.;.;Loss of methylation at K228 (P = 0.0948);Loss of methylation at K228 (P = 0.0948);.;.;.;.;.;.;.;.;.;
MVP		0.17
MPC		0.85
ClinPred		0.48	T
GERP RS		5.8
Varity_R		0.72
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-7645620;